Diffusion tensor imaging (DTI) measures the diffusion of water molecules, which reflects the microstructural organization of the tissues of interest. Previously, we have demonstrated that water diffusion parallel to the fibers, axial diffusivity, is much greater than that perpendicular to the fibers, radial diffusivity. We further demonstrated that demyelination leads to an increase in radial diffusivity and axonal damage leads to a decrease in axial diffusivity in mouse models of white matter injuries. In this proposal, we hypothesized that the in vivo DTI biomarker of axonal injury, i.e., decreased axial diffusivity, may serve as an early and accurate surrogate endpoint for outcome prediction in spinal cord injury (SCI). Axonal damage occurring in the acute period following SCI is the primary cause of long-term neurological disabilities in SCI. Thus, the primary goal of the proposed study is to determine at what post-injury time points can DTI be used to accurately predict functional (behavioral and electrophysiological) outcomes in rodent models of SCI. A translation of the use of DTI biomarker of axonal injury to cervical spondylotic myelopathy (CSM) patients will also be pursued to test the efficacy of this marker in the clinical setting. Three key questions are asked: (1) Does the in vivo DTI axonal injury biomarker reflect the underlying structural changes and predict long-term neurological outcome in SCI mice? (2) Do the in vivo DTI biomarkers correlate with axon function as measured with in vivo electrophysiology? (3) Do the in vivo DTI biomarkers accurately correlate with neurological disabilities in human cervical spondylotic myelopathy (CSM) patients? These questions will be addressed by performing the mechanistic assessment of the in vivo DTI derived biomarker of axonal injury and its application as the outcome predictor of SCI using YFP and shiverer-YFP mice (Aim 1), functional correlation of in vivo DTI biomarker of axonal injury with electrophysiology (Aim 2), and the human translation of this biomarker to CSM patients (Aim 3). PUBLIC HEALTH RELEVANCE: Spinal cord injury (SCI) can lead to devastating medical, psychological, social, and financial consequences. Experimental strategies that focus on white matter preservation during the hyperacute phase hold the greatest potential for functional recovery following traumatic SCI. The successful application of the proposed in vivo diffusion tensor imaging biomarker of white matter in the proposed studies will offer a more accurate prognostication and improved treatment stratification for SCI patients.